Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor in humans. GBM stem cells (GSCs) are a subpopulation of GBM tumor cells that show stem-cell-like properties and play a central role in tumor propagation, therapeutic resistance and tumor recurrence. We need effective therapeutic strategies to directly deplete GSCs and/or sensitize them to current GBM therapies. Developing these therapies relies on a more complete understanding of molecular drivers of GSC tumorigenicity and therapeutic resistance. This project focuses on targeting an oncogenic signaling pathway driven by the hyaluronan-mediated motility receptor (HMMR) and its downstream effector TAZ, an oncogenic transcription factor. Our central hypothesis is that HMMR and TAZ comprise a drug-targetable pathway that promotes GSC tumorigenicity and radioresistance. We propose to fill major knowledge gaps in the function of HMMR-TAZ signaling in GSCs and therapeutic applicability of HMMR-TAZ targeting in GBM. Our recent Cancer Research paper demonstrates that HMMR is a potential therapeutic target for depleting GSCs. HMMR is hyper-expressed in clinical GBM specimens. HMMR silencing effectively inhibits GSC self-renewal in vitro and tumorigenicity in vivo. Our following studies found that HMMR forms a positive feedback loop with TAZ in GSCs. This HMMR-TAZ loop signaling is essential for cell-intrinsic radioresistance in GSCs. More interestingly, HMMR-TAZ signaling also induces the spreading of radioresistance among GSCs through paracrine mechanisms likely mediated by secretory proteins. For clinical targeting of HMMR-TAZ signaling, we identified the FDA-approved drug Verteporfin (VP) as an inhibitor of HMMR-TAZ signaling and GSC tumorigenicity. VP crosses the blood-tumor barrier, supporting the feasibility to study systemic VP treatment in GBM models. Overall, our preliminary studies justify a rigorous study of autocrine and paracrine mechanisms underlying HMMR-TAZ-driven radioresistance in GSCs, and further determining the therapeutic synergy between HMMR-TAZ targeting and radiation in pre-clinical GBM models. It is also necessary to extensively study the therapeutic efficacy of VP in GSCs, molecular mechanisms of its drug action, and the therapeutic synergy between VP and radiation. We will study two specific aims: (1) determine if targeting HMMR-TAZ signaling inhibits GSC radioresistance, and further elucidate underlying molecular mechanisms, and (2) repurpose the FDA-approved drug Verteporfin to target HMMR-TAZ signaling in GBM. If successful, Aim 1 will provide novel mechanistic insights into how GBM-associated protein HMMR drives downstream transcriptional events to promote GSC tumorigenicity and therapeutic resistance. We will reveal a novel paracrine mechanism that mediates the spreading of radioresistance among GBM cells. Aim 2 will provide a solid foundation for repurposing VP for GBM therapy. VP repurposing is a novel strategy for targeting HMMR-driven oncogenic signaling in human cancers.